N-(tertiary-aminoalkyl)-2, 4-disubstituted-benzamides and their preparation



Patented Oct. 5, 1954 UNITED STATES D FF ICE'E N (TERTIARY-AMINOADKYL) -'2;,-4 -DISUB- STITUTED lesNzAMrns-s AND THEIR PREPARATION Raymond 0. Clinton, North" Greenbush, and Stanley C. Laskowski, Menands,fN.' Y., assignbrsto Sterling Drug Inc., New York,'N."Y., a'corporation of Delaware No Drawing. Application March-30, 1951, Serial NO. 2185532 where Z is a member of the group consisting of N02, NH2 and NHRs, R3 being a lower alkyl radical, R2 is a member of the group consisting of H and lower alkyl radicals, X is a lower alkylene radical and NRR1 is a lower aliphatic-like tertiary-amino radical. These compounds have useful anesthetic and other pharmacological properties, and they are als useful for the preparation of other compounds with useful pharmacological properties.

In the above general formula, the lower alkyl radicals represented by R2 and R3 have prefer ably l-6 carbon atoms, including such examples as methyl, ethyl, n-propyl, isobutyl, Z-butyl, 3-amyl, n-hexyl, and the like. The lower alkylene radical designated hereinabove as X has preferably 24 carbon atoms and has its two free valence bonds on different carbon atoms. Thus, X includes such examples as CHiCH2-,

ing -6 ring atoms, illustrated by examples such 7 as l-piperidyl, Z-methyl-lpiperidyl, 3-ethyl-1- piperidyl, 4-methy1-1-piperidyl, 2,6-dimethyl-l piper'i'dyl, lepyrrolidyl, '2-methyl-1-pyrrolidy1,

2,5-dimethyl-l-pyrrolidyl, 4-morpholinyl, and the like.

The amides of bfif'ir'ivfitioli are conveniently acids. asillustrated' by the following. series of reactions wherein 'X,'R, R1,'R'2 and Rs'have the meanings given hereinabove:

Thus, in step I, a 4-nitro-2-substituted-benzoic acid (A) 'isconverted into anN-(tertiary-aminoalkyl) 4 nitro 2 -.substituted benzamide (B), which, in step II, is reducedto yieldthe corresponding N (tertiary-aminoalkyl) -4-amino-2- siibstituted-benzami'de (C). In step III, -.the bamino compound (C) iisalkylated toproduce the IN (tertiary aminoalkyl) 4 alkylamino- 2-substitutedsbenzamide (D). The intermediate 4-nitro-2-alkoxybenzoic acids (designatedabove as (A) where R2 is alkyl) and their lower alkyl esters aredisclosed vbutznotclaimed in our copending U. S. Patent Applications Serial Nos. 168343 and 168,844 (now U. S. Patent 2,657,209), filed June 17, 1950. The N-(tertiary-aminoalkyl)- l-nitro-Z-substitutedbenzamides (designated above as (13)) are disclosed and claimed in our continuation-mepart U. -S. Patent Application Serial. No. 356,594, filed May 21, 1953.

vA specific illustration .of the foregoing series of reactions when R2 is H is the formation of N [3 (1 piperidyhpropyll 4 n butyl- ZLIHiIIO Z-hYdI'OXYbGIIZamIdB by converting =4- nitro-Z-hydroxybenzoic acid into N- [-3-(1-piperidy1) propy1] -4-nitro-2hydroxybenzamide, reducing-thisnitro compound to formthe corresponding N- [3- l-piperidyDpropyl] -4-amino-2 hydroxybenzamide and alkylating .this basic 4- -amino amide. In practicing ourinvention we carried out step I-When R2 was H by prefer-ably first converting 4.-nitro-2-hydroxybenzoic acid into its lower alkyl ester, e. g., methyl ester, and

then treating the lower alkyl ester with a tertiaryaminoalkylamine having the formula A specific illustration of the above series of reactions when R2 is a lower alkyl radical is the formation of N-(2-diethylaminoethyl) 4-n-amylamino-2-ethoxybenzamide by converting 4-nitro- 2-ethoxybenzoic acid into N-(2-diethylaminoethyl) -4-nitro-2-ethoxybenzamide which is reduced to yield N-(2-diethylaminoethyl)4-amino- Z-ethoxybenzamide and alkylating the resulting 4-amino amide. Step I where R2 is a lower alkyl radical is preferably carried out by converting the 4-nitro-2-alkoxybenzoic acid into its corresponding acid halide by treating with an appropriate halogenating agent such as thionyl chloride and treating the resulting acid halide with a tertiary-aminoalkylamine having the formula H2N-XNRR 1.

The reduction of the N-(tertiary-aminoalkyl) 4-nitro-2-substituted-benzamides (B) to the corresponding 4-amino amides (C) was carried out both by chemical methods and by catalytic hydrogenation. Suitable chemical reducing agents include iron and hydrochloric acid, ferrous sulfate and ammonia, tin and hydrochloric acid, sodium hydrosulfite, etc. Catalysts suitable when catalytic hydrogenation is used include Raney nickel, platinum, palladium, or other catalysts generally eifective to catalyze hydrogenation of nitro groups to amino groups.

The alkylation of the ll-amino amides (C) to produce the related N-(tertiary-aminoalkyl)-4- alkylamino-2-substituted-benzamides (D) preferably carried out by reductively alkylating with an alkanal. An illustration is the formation of N- [2- (2methy1-1-pyrrolidyl) ethyl] -4-n-propylamino-Z-hydroxybenzamide by treating a mixture of the corresponding 4-amino amide and propionaldehyde with chemical reducing agents, such as zinc dust and acetic acid, iron and acetic acid, or with hydrogen under pressure using catalysts such as platinum, palladium, Raney nickel, or other catalysts generally effective in reductive alkylations using aliphatic aldehydes.

Another style of synthesis of the 4-alkylamino amides (D) is the direct alkylation of the 4-amino amides (C) with alkylating agents such as methyl sulfate, methyl iodide, ethyl chloride, n-propyl bromide, isobutyl iodide, and the like, in the presence of a acid acceptor, e. g. sodium bicarbonate, potassium carbonate, etc.

Our invention includes, also, salts of the basic amides described above. Such salts include nontoxic acid addition salts and quaternary ammonium salts, which are readily prepared from the basic amides. Acid addition salts are formed by reacting the basic amides with an acid such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, lactic acid, citric acid, tartaric acid, ethanesulfonic acid, etc., to yield, respectively, the hydrochlorides, hydrobromides, hydriodides, sulfates, phosphates, sulfamates, acetates, lactates, citrates, tartrates, ethanesulfonates, etc. Our quaternary ammonium salts where Z is N02 are prepared by treating the N (tertiary aminoalkyl) 4 nitro 2 hydroXy (or alkoxy) benzamides (B) with lower alkyl and aralkyl esters of strong inorganic acids and organic sulfonic acids, such as methyl chloride, methyl bromide, methyl iodide, ethyl bromide, ethyl iodide, propyl bromide, propyl iodide, benzyl chloride, benzyl bromide, methyl was sulfate, ethyl sulfate, methyl benzenesulfonate, methyl p-toluenesulfonate, etc. yielding, respectively, the methochlorides, methobromides, methiodides, ethobromides, ethiodides, propobromides, propiodides, benzochlorides, benzobromides, methosulfates, ethosulfates, methobenzenesulfonates, metho p toluenesulfonates, etc. The corresponding N-(tertiary-aminoalkyD-4-amino-2-hydroxy (or alkoxy) benzamide quaternary ammonium salts are prepared by catalytic hydrogenation of these corresponding 4-nitrobenzamide quaternary ammonium salts. Alkylation of the 4-amino compounds yield the corresponding N (tertiary amino alkyl) 4 alkyla-mino-Z-hydroxy (or alkoxy) benzamide quaternary ammonium salts.

The following examples further illustrate our invention, but should not be construed as a limitation thereto.

EXAMPLE 1 N (2 diethylaminoethyl) 4 nitro 2 hydroxybeneamine A solution of 16.7 g. of ethyl 4-nitro-2-hydroxybenzoate and 23.2 g. of 2-diethylaminoethylamine in 250 cc. of dry toluene was refluxed for eight hours. On cooling, the reaction mixture separated into two layers, the desired product being in the deep orange-colored lower layer, which solidified when rubbed. After the toluene had been removed by distilling under reduced pressure, the orange solid that remained was dissolved in a minimum quantity of hot absolute ethanol. The solution was diluted with n-pentane, cooled, and filtered. The solid was recrystallized from absolute ethanol-n-pentane, yielding the desired product, N-(2-diethylaminoethyl) --nitro-Z-hydroxybenzamide.

This basic amide was converted into its hydrochloride salt by dissolving it in an excess of warm ethanol saturatedwith hydrogen chloride gas, warming the mixture to complete dissolution, cooling the solution and diluting it with absolute ether. Two recrystallizations of this yellow solid from absolute ethanol-absolute ether yielded N- (Z-diethylaminoethyl) -4-nitro-2-hydroxybenza-mide hydrochloride, M. P. 149.6- l50.2 C. (cor.).

AnaZ.--Calcd. for C13H19N304-HC1: C, 49.13;

H, 6.34; Cl, 11.16. Found: C, 49.35; H, 6.10; Cl, 11.12.

Additional N- (tertiary-aminoalkyl) -4-mtro-2- hydroxybenzamides which can be prepared according to the foregoing procedure by substituting the appropriate tertiary-aminoalkylamine for 2-diethylaminoethylamine include the following: N-(2-dimethylamino-1-propyl) -4-nitro- 2 hydroxybenzamide; N (2 di n butylaminoethyl) -4-nitro-2-hydroxybenzamide; N- [3- lpiperidyl) propyll 4 nitro 2 hydroxybenzamide; N [2 (2 methyl 1 piperidyl) ethyl] -4-nitro-2-hydroxybenzamide; N- [3- (l-pyrrolidyDpropyl] 4 nitro 2 hydroxybenzamide; N- [2- (2,5-dimethyl-l-pyrrolidyl) ethyl] -4- nitro-2-hydroxybenzamide; and N-[3-(4-morpholinyl) propyll -4-nitro-Z-hydroxybenzamide.

EXAMPLE 2 N (3 diethylaminopropyl) 4 nitro 2 hydromybenzamzde This preparation was carried out according to the procedure described above for Example 1, but using 16.7 g. of ethyl 4-nitro-2-hydroxybenzoate; 1350- g: of 3-diethylaminopr-opylamine and AnaZI-Caltzd. for C'isHzsNsOrHC-li- C', 52.09;-

HQ'LOO; Cl, 10.25. C1,,10.09.

Found: C, 52.23; H, 6.70;

EXAMPLE 4..

N (3 diethy'laminopropy'li 4' nitro- 2- A mixture of 42.2 g. of methyl 4enitro-2 meth oxybenzoate; 391: g. oi B-diethyIaminoprcp'yI- amine in. 500 cc. of dry xylene was refluxed for sixteen hoursp The xylenewas distilledofffunde'r. reduced pressure, the residual oil wasdis-- solved im a small amount of ethyl acetate; the solution was cooled and diluted? with n'-heXane:

whereupon: an oily. material separated. The. solvents were decanted a from the brown' oily base; N= (3 diethylaminopropyl) 4- nitro- -2 methoxybenzamide, which was converted into. its hydrochloride by dissolving it in a small quantity ofethyl acetate and treating the re sulting solutionwithan excess of ethereal hydrogen chloride whereupon there separateda The solvent was decanted and the oil was triturated with isopropanol and brown oily' material.

then diluted with absolute ether, yielding asemisolid,- but filterable, product which was -filtered and recrystallized twice from isop'ropanoli There: was thus obtained, as yellow rosettes of needles;-

N (3 diethylaminopropyll 4 nitro- 2: me'thoxyb'enzamide hydrochloride, P. 149 .1- l50.- 0. (coin).

AndL-Calcd; for C'15H23'N304 I HCI: H; 7.00: Cl, 10.25.- Found: C,- 52.16; H; 6.88; CI, 10.33.

Additional N- (tertiary-aminoalkyl) -4-nitro-2- alkoxybenzamideswhichcan be prepared accordingto the above procedure using the appropriate lower alkyl 4-nitro-2-alkoxybenz0ate and tertiary-aminoalkylamine in place of methyl l-nitro-- 2-methoxybenzoate and 3-diethy laminopropyl-- amine, respectively, include the following: N-(2'- dimethylamino 1 pro'pyl)--4-nitro-2-methoxy benzamide; N- (z di-n-butylaminoethyl) -4-nitro'- pyll -ii-nitro-Z-ethoxybenzamide;

benzamide'.

EXAMPLE 5 N- (Z-diethylaminoethyl) -4-m'tro-2-meth0xybenzamide hydrochloride A mixture of 80:0- g. of: 4-nitro-2-methoxybenzoic acid and 242g. ofthionyli chloride' was refluxed for two hours: andi the excess thionyl chloride was removed by distilling in vacuo. The residue was taken upin dry benzene andthe benzene was removed by distilling in vacuo and the remaining oily" material was dried in a vacuum desiccator over'pho'sphorus pentoxide'. This-matie-rial, thus obtained; was 4-nitro"-2 metlioxy benzoyl chloride.

A solution of 40 g.- -of '4-niti-o-2-methoxybenzoyl chloride, 2 1.6 g. of '2'-diethylamirioethylamihe85nd 300 cc. of dry benzene was war-medi whereupon there separated a gummy material, which was tritura'ted with warming until solidification re*-- sulted. Themixture was cooled in an icebath an'd diluted" to-a total volume of about one liter" with benzene. The'solid was filtered-and recrystallized from' -ab'solute ethanol n-hexane, using'deco'loriz ing charcoal, yielding N'- (Z diethyIaminOethyD 4'-nitro'2 methoxybenzamide'hydrochloride; MLPI 161.2162.7CI (C012) Ancbl;-Calcd. fbr C14H 21N3O i' HCl-i' N; 42-2 2 GT5 10.69. Found: N; 4.14501, 10.49.

Additional N- (tertiary-amino'alliyl) -4-nitro*-2*-' alkoxy benzamide hydrochlorides which can be prepared according to-the above procedure by substituting the appropriate 4-nitro-2-alkoxybenzoicacid andtertiary aminoalkylamine for 4- nitro-Z-methoxybenzoic 'acid' and '2-diethylamino'-- ethylamine; respectively, include the following: N i [2 (2 m'e'thyl 1- piperidyl) ethyl] -4-nitrd--2-- ethoxybenz'amid'e" hydrochloride; N -EB' (-1' -pyr= rolidyl)propy1l'-4-nitro 2'"- etho'xybenzamide' hwdrochloride; N- [2- (2,5 dimethyl-l-pyrrolidyl) ethyl] l-nitro-z-methoxybenzamidehydrochloride; and N-[3-(4-morpholinyl)propyl]-4-nitro 2 ethoxybenzamide hydrochloride:

EXAMPLE 6 N (3- diethylamino-Z-hydromypropyl) -4-nit'ro-- Z-methomybenzamzd A mixture of 19.3 g; of 3-diethylamino-2-hy-' droxypropylamine, 16.6 g; of sodium bicarbonate and cc. o'f'water wasstirred until a clear so1u-- tion resulted. To this solution was added'with stirring 28.4 g. of 4-nitro-2-methoxybenzoyl chlor ide in 300 cc. of chloroform at roomtemperature over a period of thirty-five minutes. The resulting solution was then stirred'for an addit'ional one hour at room temperature, dried over anhydrous calcium sulfate and the solvent removed by'distilling' in vacuo. obtained, as a dark brown, viscous oil, N-(3-di ethylamino 2 hydroxypropyl) -4-nitro-2-methoxybenzamide.

Treatment of this basic amide in absolute: ethanol solution withan excess of ethanolichy drogen'chloride (20% by weight) yielded, as'an oil, the" corresponding hydrochloride; The mix ture'was diluted with. n-hexane to ensure com-- plete precipitation of this salt. The oil was sep'--- arated fromthe solvents by decantation and then was 'di'ssolv'edin absoluteeth'anol. To the ethanol solution was added n-hexane to turbidity, where There was thus 7 EXAMPLE 7 N (Z-dz'ethylaminoethyl) -4-nitro-2-n-butoxybenzamide To a mixture of 23.6 g. of 4-nitro-2-n-butoxybenzoic acid, 100 cc. of dry benzene and 9.48 g. of pyridine was added dropwise 9.53 g. of thionyl chloride dissolved in 100 cc. of dry benzene. The solution was then heated on a steam bath for ten minutes, yielding a solution of 4-nitro-2-n-butoxy-benzoyl chloride.

This solution was added slowly, with stirring, to a mixture of 100 cc. of water, 15.1 g. of sodium bicarbonate, 11.6 g. of 2-diethylaminoethylamine and 200 cc. of chloroform, and the resulting mixture was stirred for one hour. The chloroform and water layers were separated, the aqueous layer was washed with chloroform and the chloroform washings were added to the chloroform layer. The chloroform solution was then washed with water, aqueous sodium hydroxide solution and water again, and then dried over anhydrous calcium sulfate. The chloroform was removed by distilling in vacuo, the remaining material was dissolved in 300 cc. of toluene and the toluene was removed by distilling in vacuo. The residue was then taken up in 300 cc. of benzene followed by removal of the benzene by distilling in vacuo, yielding a solid product. This solid material was recrystallized three times from n-heptane, yielding N-(2-diethylaminoethyl) -4-nitro- 2 -n-butoxybenzamide, M. P. 49.9-50.9 C. (cor.)

AnaL-Calcd. for C11H27N3O4: N, 12.45. Found: N, 12.32.

The basic amide was converted into its monohydrochloride by dissolving it in ethyl acetate and treating the resulting solution with an excess of hydrogen chloride dissolved in ether (20% by weight). Absolute ether was added to ensure complete precipitation of the hydrochloride, which separated as an oil. On cooling, the oily material gradually guinmed and finally crystallized. Two recrystallizations of this material from absolute ethanol-n-hexane yielded N-(2-diethylaminoethyl) -4-nitro-2 n butoxybenzamide hydrochloride, M, P. 133.2-134.2 C. (cor.)

Anal.Ca1cd. for C17H27N3O4'HC1Z N(NO2), 3.74; N, 11.24. 3.74; N, 11.33.

Additional N- (tertiary-aminoalkyl) -4-nitro-2- alkoxybenzamides which can be prepared according to the above procedure by substituting the appropriate 4-nitro-2-alkoxybenzoic acid and tertiary-aminoalkylamine for 4-nitro-2-n-butoxybenzoic acid and 2-diethy1aminoethylamine, respectively, include the following: N- (Z-dimethylamino-l-propyl) -4-nitro- 2 -namoxybenzamide; N-(Z-di-n-butylaminoethyl)-4-nitro 2 n propoxybenzainide; N [3- (1-piperidyl propyll -4-nitro-2-n-butoxybenzamide; N-[Z-(Z-methyl-i-piperidyl) ethyl] -4-nitro-2-n-hexoxybenzamide; N- [3-(l-pyrrolidyDpropyl]-4-nitro 2 isobutoxybenzamide; N [2- (2,5-dimethyll-pyrrolidyl) ethyl] -4-nitro-2-n-propoxybenzamide; and N- [3 (4- morpholinyDpropyl] 4 nitro-Z-n-butoxybenzamide.

Cl, 9.48; Found: Cl, 9.57; Nmop,

EXAMPLE 8 N Z-diethylaminoethyl) -4-nitro-2-npropoxybenzamide When the procedure described above for Example 7 was followed but substituting 22.5 g. of 4- nitro-2-n-propoxybenzoic acid in place of the 4- nitro-2-n-butoxybenzoic acid, there was obtained N (2 diethylaminoethyl) 4 nitro 2 npropoxybenzamide, M. P. 64.4-65.0 C. (cor.) when recrystallized from n-hexane.

Anal.--Calcd. for C16H25N3O42 N, 12.99. Found: N, 13.28.

Conversion of the basic amide to its monohydrochloride was accomplished by dissolving it in ethyl acetate and treating the resulting solution with an excess of hydrogen chloride in ether (20% by weight). The precipitated salt was recrystallized twice from absolute ethanol, yielding N (2 diethylaminoethyl) 4 nitro 2 npropoxybenzamide hydrochloride, M. P. 164.8- 167.9 C. (cor.).

Anal.Calcd. for C1sH25N304-I-IC1I Cl, 9.85; N(Ng), 3.89. Found: Cl, 9.96; N(N2)| 4.14.

EXAMPLE 9 N- (Z-diethylaminoethyl) -4-m'tm-2-nbutoarybenzamz'de methiodide To a solution of N-(2-diethylaminoethyl)-4- nitro-2-n-butoxybenzamide in 75 cc. of ethyl acetate was added 10 cc. of methyl iodide and the resulting solution was allowed to stand at room temperature. The precipitated quaternary salt was recrystallized twice from absolute ethanol, yielding N (2 diethylaminoethyl) 4 nitro- 2-n-butoxybenzamide methiodide, M. P. 136.5- 137.6 C. (cor.).

Anal.Calcd. for C17H27NsO4-CH3I: Nmop. 2.92; I, 26.48. Found: Novo 3.09; I, 26.40.

Additional N (tertiary aminoalkyl) 4- nitro-2-alkoxybenzamide quaternary salts which can be prepared according to the foregoing procedure by substituting the appropriate basic amide and an alkyl or aralkyl ester of a strong inorganic acid or an organic sulfonic acid for N- (2 diethylaminoethyl) 4 nitro 2 nbutoxybenzamide and methyl iodide, respectively, include the following: N-(2-dimethylamino-1- propyl) 4 nitro 2 n amoxybenzamide methiodide; N (2 di n butylaminoethyD- 4 nitro 2 n propoxybenzamide methobromide; N [3 (1 piperidyDpropyl] 4 nitro- 2 n butoxybenzamide ethiodide; N [2 (2- methyl 1 piperidyl)ethyl] 4 nitro 2 nhexoxybenzamide benzobromide; N [3 (1- pyrrolidyl)propy1] 4 nitro 2 isobutoxybenzamide methosulfate; N [2 (2,5 dimethyl 1 pyrrolidyDethyll 4 nitro 2- methoxybenzamide methobenzenesulfonate; and N [3 (4 morpholinyDpropyl] 4 nitro 2- ethoxybenzamide metho-p-toluenesulfonate.

Similarly, following the foregoing procedure but using the related N-(tertiary-aminoalkyl)- 4 nitro 2 hydroxybenzamides, as described in Example 1, the N (tertiary aminoalkyl) 4- nitro-2-hydroxybenzamide quaternary salts are formed, for example, N-(2-diethy1aminoethyl)- 4 nitro 2 hydroxybenzamide methiodide, N- (2 di n butylaminoethyl) 4 nitro 2- hydroxybenzamide ethobromide, N [2 (2- methyl 1 piperidyl) ethyl] 4 nitro 2- hydroxybenzamide benzochloride, N [3 (4- morpholinyl) propyl] 4 nitro 2 hydroxybenzamide methosulfate and N [2 (2,5 dimethyl 1 pyrrolidyDethyl] 4 nitro 2- hydroxybenzamide metho-p-toluenesulfonate.

EXAMPLE 10 N- (Z-diethylaminoethyl) -4-mtro-2-npropomybenzamide methiodide When the procedure described for Example 9 was followed but substituting 6.0 g. of N-(2-diethyla-minoethyl) --4 -"nitro 2 --n -;-propxybenzamide for 'the -corresponding 2-n-butoxybenzami'de, there "was obtained N (2 diethylaminoethyl) -"4 nitro "2 --'n propoxybenzamide-methiodidaM. P.'l69'-.8-'-170.5 C. (con).

AnaZ.Calcd. for GmHzaNsOrCI-BI: N-cno 3.01; I, 27.28. Found:-.N No ),-3.05; I, 27.28.

N (3-dz'ethylwminopmpyl) -4-lwmino'-2- hydrox'ybenzamzde A stirred mixture --of 565g. of powdered iron (ferrum reductum) 40000: of ethanol, 100 cc. of water and'rcc. of concentratedhydrochloric acid was brought'to a boil. Thesource of heat was removed and 56 'g. of "N (3 diethylaminopropyl) "4 nitro -"2 hydroxybenzamide hydrochloride was added pcrtionwise, with' stirring, at such a "rate as to -maintain gentle "boiling. After all of the nitro compound had been added, "the "mixture "was heated, with stirring, for anadditional twenty-five minutes. An excess of sodiumlbicarbonate (about 50 g.) was added and stirring was continued forfive minutes. The hot "reaction mixture was filtered and the filtrate wasconcentratedunder reduced pressure .to remove the rethanol andmas much water .as possible. The iresidual material was treated with toluene, theinsoluble inorganicsalts were, filtered ofi and the toluene was removedsby distilling under reduced 5 pressure, atherebyiyieming .the basic amide, (3 .diethylaminopropyl) 4 -amino-2---hydroxybenzamide, as a thick, oily.- material.

Treatment of (the basic amide in ;a; solution mf anhydrous .--ethanol with-.an excess oftetherealhydrogen chloride, yields "the :corresponding ;dihydrochloride:asa'brown: oil. ThBiSOlVGHbS were decanted and the residual :brown 'oil was -triturated with; a small 1 amount r of :absolute :ethanol until solidification rresulted. .Ihe mixture was di'lutediwith acetone, the solid was-"filteredand recrystallized from absolute ethanol, using decolorizing charcoal and adding ethanolic hydrogen chloride to thefiltrate. A'secondrecrystallizationin the same -manner yielded, 'as'fine white needles, N (3 'diethylaminopropyl) 4- amino 2 -'.hydroxybenzamide 'dihy'drochloride, M."P. l'79-.1821C. (con).

AncZZr-Calcd. .for C14H23N3Qh=2HC12 3C, 49.71; H, 745; 01, 20.96. Found: .C, 419.47; H, 7.;2'7; (Jr-20.70.

Additional N .(tertiary :aminoalkyl) ---".4- amino -.2 hydroxybenzamides which oan vbe prepared according to theaiabove :procedure but substituting :the appropriate N (tertiaryaminoalkyl) -4 nitro -'2'- hydroxybenzamide hydrochloride'for N (3 diethylaminopropyl) 4-nitro-2-hydroxybenzamide hydrochloride, include the following: N (2 -'dimethylamino- 1 propyl) 4 --amino -'2 hydroxybenzamide; N ('2 -'di n butylaminoethyl) 4 amino- 2 hydroxybenzamide; N [3 -.(1 piperi'dyl) propyl] 4 amino 2 hydroxybenzamide; N- [2 (2 methyl 1 piperidyD-ethyl] ---.4 amino -..2 hydroxybenzamide; .N [3 (@1- pyrro1idyl) .propyl] 4 famine .-2 hydroxybenzamide; N -@[2 --(2,5 --dimethyl i1 pyrrol-idyl) ethyl] -"4 amino-- 2 hydroxybenzamide; and N J53 (-4 morpholinylxpropyll "4- aminoe2-hydroxybenzamide.

N (3 -=.diethylaminopr0m/l) .4 '---amino 2 methoxybenzamide To amixture of 42.3 g. of powdere'diron, 1 cc. of concentratedhydrochloric acid and400 cc. of 50% aqueous ethanol was added portionwise with stirring 43.4 g. of N- (3-diethylaminopropyl) '-4- nitrO-Z-methQXybenZamide hydrochloride. An excess-df=sodiumbicarbonate (about 20 g'.) was added and 'themixturewas stirred for an additional thirty minutes. The ethanol was removed by distilling in vacuo,-the remaining mixture was cooled and the viscousybrowmgummy precipitate was taken up in ethyl acetate-and the resultingethyl acetatesolution-was dried over anhydrous potassium carbonate. Removal of the ethyl acetate yielded N- (3-diethylaminopropyl) 4 amino-2-meth0xybenzamide asa brown, viscous oil.

":This'basicamide was converted into its phosphoric acid addition salt-as follows: A solution of 7.0 g. of N-(3-diethylaminopropyl)-4 amino- 2-methoxybenzamide in 25 cc. of ethanol was treated with a solution of 2.89 g. of phosphoric acid in 25 cc. of ethanol. The precipitate Was recrystallizedseveraltimes, with charcoaling, from ethanol-water yielding N-(B-diethylaminopropyl) '4 amino -2 methoxybenzamide phosphate, -M.'P.21'2.0-213.1 0. (con).

Additional :N- (tertiary-.aminoalkyl) -4-arnino- 2+alkoxybenzamides which 1 can be prepared according to'the above procedure using the appropriate N (tertiary -'aminoalky1) 4- nitro 2- alkoxybenzam-ide,'in free base form or in the form of its hydrochloride addition'salt, in place of N (3 --diethylaminopr0p'yl) '4 .m'tro -.2- methoxybenzamide hydrochloride, include the following: N (2 dimethylamino -1 propyll- 4 amino 2 methoxybenzamide; N (2 din butylaminoethyl) ---4-- amino 2 methoxybenzamide;.N-- 3 ('1 --:piperidyl)propy1l 4- amino 2 ethox-ybenz-am-ide; "N [3 (2 methyl 1 -,piperidyl) propyl] 4 amino -.'2 -.meth oxybenzamide; N '[2 (2 -=methy1 l piperidyDeth'yll .4 -.amino 2 ethoxybenzamide; N [.3 (.1 pyrrolidyllpropyll- 4-- amino '2- ethoxybenzamide; N [2-- (2,5-- dimethyl '1 pyrrolidyllethyll --4 amino 2 methoxybenzam-ide; and N 3 (.4 -'morpholinyl)'propyll 4 --amino -2 ethoxybenzamide.

EXANIPLE" 13 .N- Z-diethylaminoethyl) -4-amino-2- methoscybenzamz'de .When .the .proceduredescribedin Example 12 was followedbut using 42.1 vgsof powdered iron, 1 .cc. of concentrated hydrochloric acid, 400 cc. of 50% aqueous ethanol and 41.6 g. of'N-(2-diethylaminoethyl) 4 -rnitro -2 methoxybenzamide hydrochloride, there was obtained, as a viscous, amberoil, 1N-- (2 diethylaminoethyD- 4-amino-Z-methoxybenzamide.

The phosphate 'of this basic amide, obtained as aboveinExample 12, meltedat 167.9-l70.8 C. (con).

1 1 EXAMPLE 14 N [3 (2 methyl 1 piperidyl) propyl] 4- amino 2 methoxybenzamide When the procedure described above for Example 12 was followed but using 29 g. of powdered iron, 1 cc. of concentrated hydrochloric acid, 400 cc. of 50% aqueous ethanol and 32 g. of N [3 (2 methyl 1 piperidyl) propyl]- 4 nitro 2 methoxybenzamide hydrochloride, there was obtained, as a red-orange, viscous 011, N [3 (2 methyl 1 piperidyl)propyl] 4- amino 2 methoxybenzamide.

This basic amide was converted into its dihydrochloride addition salt as follows: Ten grams of the basic amide was dissolved in ethyl acetate and treated with an excess of ethanolic hydrogen chloride. The precipitated product was collected and recrystallized several times from absolute ethanol containing a small quantity of hydrogen chloride, yielding N [3 (2 methyl 1 piperidyDpropyl] 4 amino 2 methoxybenzamide dihydrochloride monohydrate, M. P. 1438-1460 C. (cor.).

AnaZ.-Calcd. for C17H27N302'2HC1'H20I N, 10.60; Cl, 17.89; E20, 4.54. Found: N, 10.85; Cl, 17.61; E20, 4.54.

EXAlVIPLE 15 N (3 diethylaminopropyl) 4 amino 2- ethomybenzamide When the procedure described for Example 12 was followed but using 40.6 g. of powdered iron, 1 cc. of concentrated hydrochloric acid, 300 cc. of ethanol, 75 cc. of water and 39 g. of N-(3-diethylaminopropyl) 4 nitro 2 ethoxybenzamide, there was obtained, as an oily material which solidified on standing, N-(3-diethy1aminopropyl) -4-amino-2-ethoxybenzamide.

This basic amide in the form of its monohydrochloride salt melted at 204-205.6 C. (con).

AnaZ.Calcd. for C16H27N3O2-HC1: C1, 10.75; N, 12.74. Found: Cl, 10.52; N, 12.75.

EXAMPLE 16 N (2 diethylaminoethyl) 4 amino 2 nbutozcybenzamide When the procedure described above for Example 12 was followed but using 24.7 g. of powdered iron, 1 cc. of concentrated hydrochloric acid, 400 cc. of 50% aqueous ethanol and 24.8 g. of N (2 diethylaminoethyl) 4 nitro 2- n-butoxybenzamide hydrochloride, there was obtained, as an amber-colored oil, N (2 diethylaminoethyl) 4 amino 2 n butoxybenzamide.

The monohydrochloride of this basic amide melted at 199.0-199.6 C. (cor) Anal.Ca-lcd. for CnHzsNaOz-H'Cl: N, 1222; C1, 10.31. Found: N, 12.24; Cl, 10.39.

Additional N (tertiary-aminoalkyl) 4- amino 2 alkoxybenzamides which can be prepared according to the foregoing procedure by substituting the appropriate N-(tertiary-aminoalkyl) 4 nitro 2 alkoxybenzamide, in the form of its free base or hydrochloride addition salt, for N 2 diethylaminoethyl 4 nitro- 2 n butoxybenzamide hydrochloride include the following: N (2 dimethylamino 1 propyl) 4 amino 2 n amoxybenzamide; N- (2 di n butylaminoethyl) 4 amino 2- n propoxybenzamide; N [3 (1 piperidyD- propyl] 4 amino 2 n butoxybenzamide; N [2 (2 methyl 1 piperidyDethyl] 4* amino 2 n hexoxybenzamide; N [3 (1- pyrrolidyDpropyl] 4 amino 2 isobutoxybenzamide; N [2 (2,5 dimethyl 1 pyrrolidyDethyl] 4 amino 2 n propoxybenzamide; and N [3 (4 morpholinyl) propyl] 4- amino 2 n butoxybenzamide.

EXAMPLE 17 N (2 diethylaminoethyl) 4 amino 2 npropoacybenza'mide When the procedure described above for Example 12 was followed but using 28.0 g. of powdered iron, 1 cc. of concentrated hydrochloric acid, 400 cc. of aqueous ethanol and 30.0 g. of N (2 diethylaminoethyl) 4 nitro 2 npropoxybenzamide hydrochloride, there was obtained as a viscous, amber-colored oil, N (2 diethylaminoethyl) 4 amino 2 n propoxybenzamide.

The hydrochloride of this basic amide melted at 232.7233.7 C. (001:).

AnaZ.Calcd. for CreI-IzvNsOz-HCI: C1, 10.75. Found: N, 12.72; C1, 10.88.

EXANIPLE 18 N-(Z-dzethylaminoethyl) -4-amin0-2-n-pr0po:cy-

benzamide methiodide A solution of 4.0 g. of N-(2-diethylaminoethyl) 4-nitro-2-n-propoxybenzamide methiodide in 150 cc. of absolute ethanol was reduced catalytically with hydrogen in the presence of 200 mg. of platinum oxide, the reduction being carried out for a period of eight hours at 50 C. The reaction mixture was filtered and the filtrate was concentrated in vacuo to yield an orange, gummy material which was taken up in absolute ethanol. On cooling the ethanol solution, there separated crystalline material which was recrystallized, with charcoaling, from absolute ethanolether. A second recrystallization from absolute ethanol, with decolorization using charcoal, yielded N-(Z- diethylaminoethyl) 4 amino 2 n propoxybenzamide methiodide, M. P. 138.814l.0 C. (con).

Anal.-Calcd. for C1sH2'7N3O2-CH3 I: N, 965; I, 29.15. Found: N, 9.66; I, 28.99.

Additional N (tertiary amino) 4 amino- 2-alkoxybenzamide quaternary salts which can be prepared according to the above procedure by substituting the appropriate N-(tertiary-aminoalkyl) 4 nitro 2 alkoxybenzamide quaternary salt for N-(2-diethylaminoethyl) -4-nitro-2- n-propoxybenzamide methiodide include the following: N-(2-dimethylamino-l-propyl) -4-amino- 2-n-amoxybenzamide methiodide; N-(2-di-nbutylaminoethyl) 4 amino 2 n propoxybenzamide methobromide; N [3 (1 piperidyl)propyl] 4 amino 2 n -butoxybenzamide ethiodide; N [2 (2 methyl 1 piperidyl)- ethyl] 4 amino 2 n hexoxybenzamide benzobromide; N [3 (1 pyrrolidyl) propyl]- 4 amino 2 isobutoxybenzamide methosulfate; N [2 (2,5 dimethyl 1 pyrrolidyDethyll- 4 amino 2 methoxybenzamide methobenzenesulfonate; and N [3 (4 morpholinyD- propyl] 4 amino 2 ethoxybenzamide methop toluenesulfonate.

Similarly, following the foregoing procedure but using the related N-(tertiary-aminoalkyl)- 4 nitro 2 hydroxybenzamide quaternary salts, as described in Example 9, in place of N (2 diethylaminoethyl) 4 nitro 2 n propoxybenzamide methiodide, the N-(tertiary-arninoalkyl) 4 amino 2 hydroxybenzamide quaternary .zsalts areiiormed. iioreexamnle. [New- .diethylaminoethyl) .4 airline .2 :hydmxy benzamide methiodide, N-- .(2 di-n-tbutrlaminoethyl) -14 -ramino 2 -zhydroxybenzamide ethobromidaN .122 :(2- -;methyl--. -:n :per.idy1 ethyl] 4 amino '2 .hydroxybenzamide benzochloride, N ;[-3-- (4 m rpholinyllp epy l 4 :amino :2 ydroxyhenzamideameth su fate and .N 1L2 (2.5 --.di.methy p rrcl drhethyl] '4- -.amino 2 .hydroxybenzamidemethop-toluenesulfonate.

N (2 ,.dz'.ethylaminoetityl) =-.4 -.amino- 2 571.-

butomybenzamide methiodide When the procedure described above for Example 18 was followed but substituting 4.5 g. of N (2 diethylaminoethyl) 4 nitro 2 nbutoxybenzamide methiodide; for .the 2-n-pr0poxy homolog and carrying out the hydrogenation for four hours at 50 0., there wasvobtained N-(Z-diethylaminoethyl) 4 amino 2 n butoxybenzamide methiodide, M. iP. 31:73.;3-1745 '('cor.).

Anal.eCalcd. :for :C1'7H29N3@21CH3 I: N, .935; 0.4811; H, 7.17. "Found: "N, 9.28; 70,4802; :H, 6.97.

.EXAMPDEQO N (3 diethylaminopropyl) '4 n -butylamino'- 2 ,methozcybenzamide To .'a :hot 1 stirred :mixture -.o.f 8.0 of .N-( 31diethylaminopropyl) 4 amino 2 methoxybenzamide, 7.49 g. of zinc dust, 7.04 g. of glacial acetic acid and 100 cc. of dry benzene was added 2.50 g. of n-butyraldehyde dissolved in 25 cc. of dry benzene over a period of about fifteen minutes. After the mixture Chad been stirred under reflux for one and one-half hours, an additional 1 cc. of n butyraldehyde was added and refluxing, with;s.ti.rring, wasecontinued ,fcr-amaddition-al .threeand-one-halfa hours. IEhezUnx:v and zinc {acetate was -.fi1tere.d off and washed with hot dilute .acetic acidandrbenzene. .IIheeooled filtrate was made basic to litmus withmoncentrated .ammonium hydroxide, .the benzene .layer was separated and :the aqueous .layer .was extracted with benzene. .TheJoenzene'extraQts were combined with the benzene .layer .and the ,re ul in b nzene solution was dried ;o.v.-e.r --anhydrous .pQtassium.-.carb0nate. :Reynoval of the benzene by distilling in vacuo ,yieldedN-(B-diethylamino ropyl) 4 -n --.buty1amino .2- methoxybenzamide as a strawe cnlored.oilyrmaterial.

'flfhis basic amide .waspurifiemby. converting it into its rhydrochloride; salt, -.di,ss.olvihg .the .hydrochloride, in absolute ,ether, treating the ,hot.ether solution .with ,decolorizingoharcoal, .filtering .the hot mixture and removing ,theeetherby.distilling in vacuo. The hydrochloride was .then ..dissolved in .water, the aqueous solution waspmade basic .to litmus with concentrated cail'unorlium hydroxide andthe .basic amide thatseparated wastaken up in .n-hexane. On cooling, .this solution yielded an oily product which.crystallized on,standing. This solid was filtered and ;.recrystalliz.ed from benzene ,n hexane, yielding N--- (3 ,diethylaminopropyl) 4 n butylamino 2 methoxybenzamide, M. P. 58.459.8 'C. (cor.).

AnaZ.-Calcd. for C19H33N3Q21C, 68.02; H, 9.91; N, 12.53. Found: C, 68.08; H, 9.79; N, 12.33.

Additional N (tertiary aminoalkyl) 4- alkylamino 2 alkoxybenzamides which can be prepared according -.t0 -.-the -,above procedure by substituting the appropriate :N-(tertiary-aminoallgyl) 4 amino 2 alkoxybenzamide and alkanalfor N (3 diethylaminopropyl) 4-' amino 2 -methoxybenzamide and n butyraldehyde,- rrespectively, *2 include: the (following: :N. (2- n.- butylammoethyl) 4 an I lpropylamino --,:2- methoxybenzamide; .'N -[-3 42 --.inQth:y1-- :1.- piperid bpropyll :4

hexylamiho .2- methoxybenzamide; ;N ;[.-3 (1 --:nyrmlidy1)-- propyl] ;4-:n -.-:b.utylamino--2- ethoxyhenzamide; 5N (-2 dimethylamino .21 rpropyl) 14-. n ylaminom 2 --:n-- amoxybenzamidemand N [3 (4 morpholinyDpropyl] 4 --.n -:butylamino 2 an ---:butoxybenzamide.

.eltema'tirely. .the re oing rnrocedune (can be carri d out u in .directiallsylating:means. :Eor example, by alkylating N (2 diethylaminoethyl) 4 amino 2 n butoxybenzamide with methyl iodide or ethyl'bromide, there is obtained, respectively, N (2 diethylaminoethyl) 4 methylamino 2 n butoxybenzamide and N (2 diethylaminoethyl) 4- ethylamino 2 -.n -.butoxybenzamide.

When the above procedure for Example 20 is followedrbut using;N-- 2 diethylaminoethyl).- 4-: amino -12 n .propoxybenzamide:methioditie in ,place ."of N .(3 diethylaminopropyl) :4- amino --:2 -=methoxybenzamide,:there isrohtained ---.'(2- diethylaminoethyl) 4 .-:n -zbut-ylam-lno- 2 an .-:propoxybenzamide methiodide.

.1?ollovving the :procedure ;ab ove {for Example :20 but nsingN (2 -1die.thylaminoeth-y1) i 14-. amino- 2 -zhydr.oxyhenzamide :or :its methiodide tint-place of 2N 03 -.dietbylaminopropy1) .4 amino 2? methoxybenzamide;:thererisohtained(N d2 -;di-

ethylamincethyl) a hn .butylamino ahydroxybenzamide .:.or its .i methioidide, zrespectively.

EXAMPLE 21 N (4 diethylcminobutyl) 4 -m butylamino- 2-methoxybenzamide When the procedure described above in Example 20 was followed-but using 20.0 g. of N-(4- die hylaminobutyl) 4 ,aamino .-2 tmethoxw benzami ent7t85 g. ofizinc dust,.rfiisss-nof'glacial acetic acid, .15.!)4 e. -.of n-.butyra1dehyde :and .300 of y nedthere .WesQbtained (th 56.0 responding -n-.b; ty1amino basic amide, whi h was urifiedra dn mammal-20 .thmu heitsmyhmr chloride salt. The product thus obtained, N-(4- diethylaminobutyl) 4 n butylamino 2- methoxybenzamide, was an amber-colored, viscous oil.

Anal.-Ca1cd. for C2QH35N302I C, 68.73; H, 10.09; N, 12.02. Found: C, 68.63; H, 10.26; N, 12.00.

N -l[j3 (2- me h -1 -.pip ridyll t nwll .4--;nbutylaminoaz-methozrybenzamide When the proceduredescribed above for "Ex meth xy enzamide, .429 ,g. .of nvhutyrald hyde.

12185 g. of zinc dust, 12.1 g. of glacialacetlciacid and 300 cc. of dry benzene, there was obtained, after purification through itshydrochloride salt, N [3 (2 methyl 1 piperidyDpropyl] 4 nbutylamino 2 metho-xybenzamide, a viscous. straw-colored oil.

AnaL-Calcd. for CmHasNsOznC, 69.76; H, 9.75; N, 11.62. Found: .Q,:.6.9.93;.;H,-,9,58; N, 11.31.

15 EXAMPLE 23 N (3 diethylaminopropyl) 4 n amylammo- Z-methomybenzamide where Z is a member of the group consisting of NH: and NH(lower alkyl) R2 is a member of the group consisting of H and lower alkyl radicals, X is a lower alkylene radical having at least two carbon atoms and having its two free valence bonds on different carbon atoms, and NRR1 is a member of the group consisting of lower dialkylamino, l-piperidyl, (lower alkylated)-1-piperidyl, l-pyrrolidyl, (lower alkylated) -1-pyrrolidyl and 4-morpholiny1, and its non-toxic acid addition and quaternary ammonium salts.

2. An N (dialkylaminoalkyl) 4 amino 2- alkoxybenzamide having the formula ITIHi where X is a lower alkylene radical having at least two carbon atoms and having its two free valence bonds on different carbon atoms, and R, R1 and R2 are each lower alkyl radicals.

3. An N (tertiary-aminoalkyl) 4 amino- 2-alkoxybenzamide having the formula NHn ONH-X-NRRl where X is a lower alkylene radical having at least two carbon atoms and having its two free valence bonds on different carbon atoms, R2 is a lower alkyl radical and NRR1 is a (lower alkylated)1- piperidyl radical.

4. A compound according to claim 2 where XNRR1 is a 2-diethylaminoethyl radical.

5. A process of preparing an N-(tertiary-aminoalkyl)-4-amino-2-substituted-benzamide hav ing the formula where R2 is a member of the group consisting of H and lower alkyl radicals, X is a lower alkylene radical having at least two carbon atoms and having its two free valence bonds on different carbon atoms, and NRR1 is a member of the group consisting of lower dialkylamino, l-piperidyl, (lower alkylated) 1 piperidyl, 1 pyrrolidyl, (lower alkylated)-l-pyrrolidyl and 4-morpholinyl, which comprises treating the corresponding N (tertiary aminoalkyl) 4 nitro 2- substituted-benzamide with a reducing agent effective to reduce nitro groups to amino groups.

6. A process of preparing an N-(dialkylaminoalkyl)-4-amino-2-alkoxybenzamide having the formula where R, R1 and R2 are each lower alkyl radicals and X is a lower alkylene radical having at least two carbon atoms and having its two free valence bonds on difierent carbon atoms, which comprises treating the corresponding N (dialkylaminoalkyl)-4-nitro-2a1koxybenzamide with a reducing agent eifective to reduce nitro groups to amino groups.

7. A process of preparing an N-(tertiary-aminoalkyl) -4-amino-2-alkoxybenzamide having the formula NHZ where R2 is a lower alkyl radical having at least two carbon atoms and having its two free valence bonds on different carbon atoms, X is a lower alkylene radical and NRR1 is a l-piperidyl radical, which comprises treating the corresponding N (tertiary aminoalkyl) 4 nitro 2 alkoxybenzamide with a reducing agent effective to reduce nitro groups to amino groups.

8. A process according to claim 6 where X--NRR1 is -CH2CH2N(C2H5) 2.

9. N (2 diethylaminoethyl) 4 amino- 2-n-propoxybenzamide.

10. N (2 diethylaminoethyl) 4 amino- 2-n-butoxybenzamide.

11. A process of preparing N-(Z-diethylaminoethyl) 4 amino 2 n propoxybenzamide which comprises treating N (2 diethylaminoethyl) 4 nitro 2 n propoxybenzamide with a reducing agent efiective to reduce nitro groups to amino groups.

12. A process of preparing N (2 diethylaminoethyl) 4 amino 2 n butoxybenzamide which comprises treating N (2 diethylaminoethyl) 4 nitro 2 n butoxybenzamide with a reducing agent effective to reduce nitro groups to amino groups.

13. An N (dialkylaminoalkyl 4 amino- Z-hydroxybenzamide having the formula where X is a lower alkylene radical having at least two carbon atoms and having its two free valence bonds on different carbon atoms, and R and R1 are each lower alkyl radicals.

14. A compound according to claim 13 where NRR1 is a diethylamino radical.

15. N (3 diethylaminopropyl) 4 amino- 2 hydroxybenzamide.

16. An N (dialkylaminoalkyl) 4 alkylamino 2 alkoxybenzamide having the formula NH (lower alkyl) where X is a lower alkylene radical having at least two carbon atoms and having its two free valence bonds on different carbon atoms, and R, R1 and R2 are each lower alkyl radicals.

17. An N (diethylaminoalkyl) 4 n butylamino 2 alkoxybenzamide having the formula NHCHQCHZCHQCHS References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,073,100 Eisleb Mar. 9, 1937 2,490,780 Clinton et a1. Dec. 13, 1949 2,551,647 Steiger May 8, 1951 OTHER REFERENCES Chemical Abstracts, vol 44 (1950) p. 10138. (Abstract of McIntyre et al.-Nebraska State Med. J. vol. (1950) pp. to 104.

Jensen et al.: Acta Chemica Scand. vol. 2 (1948) pp 220 to 224.

Bing et al.: Acta Pharmacol. v01. 4 (1948) pp. 199 to 204. 

1. A MEMBER OF THE GROUP CONSISTING OF AN N-(TERTIARY-AMINOALKYL) -2,4-DISUBSTITUTEDBENZAMIDE HAVING THE FORMULA
 19. N-(3-(2-METHYL-1-PIPERIDYL) PROPYL)4-AMINO-2-METHOXYBENZEMIDE. 